The overall goal of our HVTN Laboratory Program is to conduct state-of-the-art laboratory-based clinical research and evaluation through the HIV Vaccine Trials Network that will lead to the development of a safe and efficacious HIV vaccine. To accomplish this goal, we propose six Specific Aims. In Aim 1, we will build upon, improve and enrich the current infrastructure and operations of the HVTN Laboratory Program to provide the leadership and administration to conduct high quality laboratory-based vaccine research and evaluation. In Aim 2, we will execute protocol-related validated endpoint laboratory studies in a GLP setting and comprehensive exploratory studies that will provide unambiguous measurements of vaccine immunogenicity. In Aim 3, we will apply FDA-compliant, validated assays as well as a broad range of innovative approaches to measure vaccine efficacy in large-scale phase lib/Nil trials and to improve understanding of the correlates of HIV protection. In Aim 4, we will explore strategies to induce and improve measurements of innate and mucosal immunity as well as anti-vaccine responses that have the potential to augment or dampen vaccine efficacy. We propose in Aim 5 a rigorous Laboratory QA/QC and operations program overarching all aspects of the HVTN Laboratory studies. Finally, in Aim 6 we will provide leadership and expertise as needed to facilitate and participate in investigations with other HIV clinical trials networks. Headquartered at FHCRC, the HVTN laboratory Program will coordinate its activities seamlessly with the HVTN Core Leadership and the SDAC (SCHARP) and with the DAIDS Vaccine Clinical Branch.